There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in systemic autoimmune disease. Innate immunity plays an indispensable role in both idiopathic and environmentally induced systemic autoimmunity, with the requirement for endosomal toll-like receptors and/or UNC93B1 providing a unifying mechanism in idiopathic, pristane- and mercury-induced autoimmunity. However there are clear differences in other required innate molecular and cellular components that mediate disease development. These differences represent a significant barrier to our understanding of the totality of the autoimmune disease process and its possible treatment. Both silica and mercury have been implicated in the expression of autoimmune disease in humans and animals. Although there is a paucity of information on mechanisms in silica-induced autoimmunity, the linkage between silicosis and the risk of developing clinical connective tissue diseases such as SLE, suggest that immunological checkpoints in silicosis may contribute to silica-induced autoimmunity. Murine silicosis is influenced not only by type 1 interferon but also by IL-17. The NLRP3 inflammasome and caspase-1 are also required for silicosis and their importance to silica-induced autoimmunity is supported by our preliminary studies showing that caspase-1 is required for autoantibody induction. In contrast our studies suggest that mercury-induced autoimmunity does not require type 1 interferon, NLRP3 or caspase-1. Based on these observations we hypothesize that distinct components of the innate immune system regulate the severity of systemic autoimmunity induced by specific xenobiotics. We propose to address this hypothesis in four specific aims:- Aim 1) Are Scavenger Receptors (SRs) Essential for Xenobiotic-Induced Systemic Autoimmunity? Aim 2) Does TLR mediated Type I interferon Regulate Xenobiotic-Induced Systemic Autoimmunity? Aim 3) Does xenobiotic-induced autoimmunity arise by inflammasome dependent or independent mechanisms? and Aim 4) Is proinflammatory IL-1 required for IFN-? dependence of xenobiotic-induced autoimmunity? Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new insights into the processes that instigate and drive systemic autoimmunity.